ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)
pyridine dihydrochloride
salt] is a selective neuronal
nicotinic receptor (NNR) modulator with cognitive enhancing properties in animal models of cognitive functioning. Amongst NNR subtypes,
ABT-089 shows selectivity for the
cytisine binding site on the alpha4beta2 receptor subtype as compared to the
alpha-bungarotoxin (alpha-BgT) binding sites on the alpha7 and alpha1beta1deltagamma receptor subtypes. In functional in vitro electrophysiological and
cation flux assays,
ABT-089 displays differential activity including agonism, partial agonism and antagonism depending upon the NNR subtype and assay.
ABT-089 is as potent and efficacious as (-)-
nicotine at evoking
acetylcholine (ACh) release from hippocampal synaptosomes. Furthermore,
ABT-089 is neuroprotective against excitotoxic
glutamate insults, with even greater potency seen after chronic treatment. Similarly,
ABT-089 is effective in models of cognitive functioning, including enhancement of baseline functioning as well as improvement of impaired cognitive functioning seen following septal lesioning and natural aging. In neuroprotective assays the compound is most potent by chronic administration. In stark contrast to the positive effects in the cognitive models,
ABT-089 shows little propensity to induce adverse effects such as
ataxia,
hypothermia,
seizures, cardiovascular or gastrointestinal side effects. Together these data suggest that
ABT-089 is a NNR modulator with the potential for treating
cognitive disorders with markedly limited adverse cardiovascular and gastrointestinal side effects.